Genetic variations in individuals can influence how well antibody-based therapies work, according to researchers at the University of Basel in Switzerland. These therapies are used to treat diseases such as cancer, rheumatic disorders, and multiple sclerosis by targeting specific structures in the body.
The study, published in Science Translational Medicine, was conducted by teams from the University of Basel's Departments of Biomedicine and Biozentrum. Led by Dr. Rosalba Lepore and Professor Lukas Jeker, the research involved analyzing genetic sequences from thousands of people using computer-assisted methods. The focus was on amino acids located at antibody docking sites—known as epitopes—on target proteins.
A single change in an amino acid at these docking sites can prevent antibodies from binding effectively. The team studied 87 therapeutic antibodies that are commonly used for cancer and autoimmune diseases. They found a significant number of naturally occurring variations in epitope sequences.
"These variants do not contribute to the disease themselves," said Rosalba Lepore. "The majority of them do not even impair the function of the protein in question, but they can render the treatment ineffective."
Through computer modeling and laboratory experiments on four medically important target proteins and their corresponding antibodies, researchers discovered that while one antibody might fail to bind due to a variant, another antibody targeting a different region could still be effective.
Although these genetic variants are relatively rare—with less than one person in a hundred typically affected—the findings suggest that doctors should consider genetic testing if an antibody therapy is not working as expected. Professor Jeker emphasized this point: "It is important for doctors to consider this aspect if a treatment is not working."
Many antibody-based treatments are costly; for example, CAR T-cell therapies used against certain cancers come with high expenses. Co-first author Dr. Romina Marone noted: "A genetic test to determine whether the treatment can actually work would be a small cost in comparison." Rosalba Lepore added that screening patients’ binding sites before clinical trials could also be valuable: "For clinical studies, testing the binding site of the antibody therapy in the study participants first could be worthwhile."
The study also highlighted geographical differences: some protein variants are very rare in Europe but may occur more frequently elsewhere, potentially affecting treatment effectiveness regionally.
"There is still much less genetic sequence data available for some regions of the world than there is for Europe or North America," said bioinformatician Rosalba Lepore. "As a result, we may be missing clusters of such treatment-relevant variants in certain population groups." She pointed out that more comprehensive global data collection is needed.
